Alzheimer's disease (AD) is a devastating neurodegenerative disease, characterized by beta amyloid, tau pathology and irreversible cognitive loss. Neither clear understanding of the pathological process nor the effective treatment of AD is available at present. Recent research indicates that increased endoplasmic reticulum (ER) calcium release from IP3R and ryanodine (RyR) calcium channels precedes amyloid deposition, tau pathology, neuronal loss, and cognitive impairments in AD. Targeting these early pathogenic processes may prove to be a successful therapeutic strategy of AD. Excessive calcium release from IP3R and hyperphosphorylation of tau via GSK3b upregulation is stabilized by lithium. RyR increases calcium release and impaired synaptic plasticity is stabilized by dantrolene, a novel RyR-channel stabilizer. The purpose of this project is to explore the role of IP3R and GSk3b and that of RyR-mediated calcium increase in synaptic dysfunction and AD pathological process and whether lithium and dantrolene derivatives can stabilize ER calcium channels and block synaptic dysfunction and AD pathology by pursuing two objectives below. Objective 1: Demonstrate that lithium serves as a neuroprotective agent during early stage of AD pathogenesis. We will treat AD mouse models (3xTg-AD) and controls with lithium for 4 weeks, and then examine biochemical changes indicative of histopathological cascades of AD, hippocampal synaptic integrity and also examine hippocampal synaptic plasticity and restoration of calcium signaling in CA1 hippocampal neurons. Objective 2: Examine whether dantrolene derivatives block impaired synaptic function and integrity. We will treat 3xTg-AD and control mice with the derivatives for 4 weeks, and then examine synaptic plasticity and integrity and restoration of calcium signaling in CA1 hippocampal neurons. This project could open a pathway to the development of an effective treatment of veterans with AD.